Studies of infections complicating children with neoplastic disease and HIV infection focus on development of new approaches to treatment of invasive fungal infections, rapid molecular detection, and augmentation of host defenses. In developing new approaches for treatment of invasive fungal infections in immunocompromised children, we demonstrated through a translational research program that lipid formulations of amphotericin B (e.g. amphotericin B lipid complex (ABLC) and Ambisome) were more effective and less toxic than conventional antifungal therapy in experimental disseminated candidiasis and invasive pulmonary aspergillosis, providing a rational foundation for clinical trials. We then conducted phase I-II studies in immunocompromised patients, leading to FDA approval for the first lipid formulation of amphotericin B in the U. S. in children and adults. We also completed the first phase III randomized double-blind controlled trial of empirical Ambisome versus amphotericin B in persistently febrile neutropenic patients. In improving the early diagnosis and therapeutic monitoring of disseminated candidiases, we developed a rapid automated system for detection of d-arabinitol metabolite from Candida spp., in experimental disseminated candidiasis and in a multicenter clinical trial. We further demonstrated the potential utility of PCR and single strand conformational polymorphism (SSCP) for recognition of medically important opportunistic fungi. In developing new approaches for augmenting host defenses, we demonstrated that MCSF augments pulmonary host defenses against experimental invasive aspergillosis, that neutralization of IL-4 and IL-10 improves host response against aspergillosis, and that IL-15 is a potent activator of superoxide production (not through upregulation of NADPH-oxidase genes) and of antifungal activity against Candida in elutriated monocytes. We also showed that GM-CSF and interferon-g reverse corticosteroid-induced immunosuppression of antifungal neutrophil and monocyte activity against Aspergillus fumigatus. In developing approaches for enhancing mucosal defenses, we found that the mucosal peptides, cecropin, histatin, and adrenomedullin-related peptides have potent antimicrobial activity that may be translatable into novel approaches for gene therapy. In exploring the genetic molecular basis for altered host response, we also defined the molecular regulation of the phagocyte specific NADPH-oxidase, a complex enzyme system responsible for generating oxygen radicals, critical for antimicrobial and tumoricidal activities. We have characterized three of the genes, p40, p47, and p67-phox, with the intention of studying the regulation of the genes as a model for modulating host defenses determining that there are at least two highly homologous pseudogenes of p47-phox gene which have been physically mapped to within several hundred kilo bases. This explains the overrepresentation of the GT deletion seen in nearly all patients with p47-phox deficient chronic granulomatous disease. We are further defining the molecular basis for altered mannose binding protein and FcgR in contributing to immune impairment. These studies pride new approaches for more effective and safer management of severe infections in immunocompromised children.